Therapy of toxoplasma encephalitis in AIDS patients requires long-term administration of antitoxoplasma agents to adequately treat the infection and prevent relapse. There are very few regimens that have demonstrated efficacy in treating toxoplasmosis. The best evaluated regimen is a combination of pyrimethamine plus sulfadiazine. Unfortunately, this regimen is associated with a high incidence of adverse reactions in AIDS patients, frequently requiring discontinuation of therapy. The combination of pyrimethamine and clindamycin also appears effective but again is associated with a high incidence of adverse reactions. 566C80 is a hydroxynaphthoquinone with very effective anti-protozoal, including anti- toxoplasma and anti-malaria, activity in vitro and in animal models of infection. We are conducting a study to evaluate the efficacy of 566C80, also called atovaquone, in the treatment of toxoplasmosis in AIDS patients. This study initially began with treatment with 566C80 as a single agent. Eight patients were enrolled, seven of whom improved and one of whom remained stable. Two patients ultimately relapsed. The remainder died from AIDS-related complications with no evidence of relapse during the follow-up period of up to sixty weeks. Subsequently, based on in vitro studies demonstrating synergy between 566C80 and pyrimethamine in animal models, we are evaluating this combination in AIDS patients with toxoplasmosis. Six patients have enrolled in this phase of the study to date. Two patients did not respond; both had low serum 566C80 levels. The remaining four responded; three patients continue on therapy for 10-48 weeks with sustained improvement. One patient died at week 6 with progressive Kaposi sarcoma with improved toxoplasmosis. The goal of this study is to develop an effective alternative therapy for treating toxoplasmosis, which is one of the most common CNS infections in AIDS patients.